ABSTRACT HPV16 is causative in 90% of HPV+ oropharyngeal cancers, which now represent up to 70% of all oropharyngeal cancers. Importantly, the incidence rate of HPV+ oral cancers is steadily increasing worldwide and in the United States. While prophylactic vaccines will curb HPV cancer incidence in the future, there is an urgent need to study HPV16 cancer pathogenesis to reduce the risk of cancer for populations already infected with HPV. In order to improve the prevention and treatment of this disease, we must better understand the early steps of HPV tumor pathogenesis in the oral cavity. Current knowledge implicates HPV E7 oncogene into early stages of oral carcinogenesis by targeting the host-cell tumor suppressors of retinoblastoma (RB) family proteins that includes pRb, p107 and p130. HPV16 E7 binds RB proteins directly through its LxCxE motif, and inactivates their ability to maintain G0/G1 checkpoint. Importantly, there is compelling evidence showing that inactivation of the RB family is essential for early steps of oral carcinogenesis but the molecular mechanisms of this effect of E7 are not fully understood. Recent studies show that E7 disrupts DREAM, a transcriptional repressor complex that can include p130 or p107, but not pRb. DREAM (Dimerization partner, RB-like, E2F And MuvB) assembles in the G0/G1 stages of the cell cycle when p130 binds the MuvB core consisting of LIN9, LIN37, LIN52, LIN54 and RBBP4 proteins, and represses genes required for cell cycle progression and DNA repair. In S-phase, DREAM disassembles, and the MuvB core is recruited by B-Myb to form the MMB (Myb-MuvB) complex required for G2/M gene expression. MuvB core LIN52 protein binds directly to both p130 and B-Myb, and serves as an adaptor for MuvB core recruitment. An E7-like LxSxE motif in the LIN52 N-terminus mediates its interaction with p130, whereas its C-terminus mediates the B-Myb binding. Replacement of the LxSxE sequence in LIN52 with LxCxE results in the LIN52S20C mutant that competes with E7 for p130 binding and restores DREAM in HPV+ cancer cells, causing growth suppression. Conversely, mutation of the S28 phosphorylation site in LIN52 (LIN52S28A mutant) completely abolishes DREAM formation, resulting in increased cell proliferation. Loss of DREAM repression of cell cycle dependent genes could be essential for aberrant cell proliferation leading to hyperplasia and then cancer. However, it is not known whether this mechanism could play a role in early stages of HPV oral tumorigenesis. Our proposed study is aimed at closing this gap in knowledge by applying our new findings and mouse genetic models for understanding the pathogenesis of HPV+ oral cancers.